We previously cloned p63, a p53 family member, and subsequently investigated its role in cancer. We were the first to identify p63 amplification and over expression in human squamous cell carcinoma and demonstrated that forced p63 expression led to increased proliferation and tumor growth. Moreover, we showed that WT p53 bound deltaNp63 leading to p63's caspase-dependent degradation. We then demonstrated that (Np63 associated and inhibited the B56alpha regulatory subunit of protein phosphatase 2A (PP2A), leading to inhibition of GSK3beta-mediated phosphorylation of beta-catenin, and in turn, nuclear accumulation of beta- catenin and dramatic activation of beta-catenin signaling. Recently, we found that p63 proteins undergo phosphorylation and degradation following exposure to DNA damaging agents. This revised proposal for renewal is now centered on further understanding the underlying function of p63 in response to the DNA damaging agent cisplatin. We discovered marked p63 degradation after cisplatin exposure accompanied by p53 stabilization. Moreover, we found an interesting correlation between p63 levels and cisplatin response in primary head and neck cancers. We hypothesize that p63 (like p53 and perhaps p73) is a critical determinant of the cellular response following DNA damage. We will explore putative phosphorylation sites on p63 that result in its degradation after cisplatin exposure 2) dissect the kinase cascade responsible for p63 phosphorylation 3) identify new p63 transcriptional targets after cisplatin exposure and modification and 4) define a consensus p63 cis binding site and differences in binding after modification. Thus, understanding the molecular mechanisms underlying this p63 response will lead to a deeper understanding of p63 function and could lead to improvements in current therapeutic approaches for human head and neck cancers.